Penam derivatives

ABSTRACT

A compound of the general formula: ##STR1## wherein R 1  is amino or a conventional, pharmaceutically acceptable acylamino, R 2  is carboxy or a conventionally protected carboxy, X is --S-- or ##STR2## R 3  is lower alkyl and Y&#34; is a residue of a strong nucleophile selected from the group consisting of azido, thiocyanato, lower alkyanoylthio and piperidinothiocarbonylthio.

This is a division, of application Ser. No. 867,623, filed Jan. 6, 1978,which is a Divisional of Ser. No. 648,491 filed Jan. 12, 1976 now U.S.Pat. No. 4,084,049 which is a Divisional of Ser. No. 407,962, filed Oct.19, 1973, now U.S. Pat. No. 3,954,732.

Having now generally described the invention, a further understandingcan be attained by reference to certain specific examples which areprovided herein for purposes of illustration only and are not intendedto be construed as limiting unless otherwise so indicated. ##STR3##

EXAMPLE 1

2,2,2-Trichloroethyl2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(0.65 g) was dissolved in chloroform (15 ml). To this solution was addedcupric chloride (0.16 g) and then the mixture was stirred for 8 hours atroom temperature. Precipitates were filtered off and the filtrate waswashed with a saturated sodium bicarbonate aqueous solution and thenwith water and thereafter dried over magnesium sulfate. The solvent wasdistilled off to give oily 2,2,2-trichloroethyl2-chloromethyl-2-methyl-6-(2-phenoxyacetamido)penan-3-carboxylate (0.56g).

Infrared Absorption Spectrum (Film) 3350, 1785, 1760, 1685 cm⁻¹.

EXAMPLE 2

2,2,2-Trichloroethyl2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(0.63 g) was dissolved in chloroform (15 ml). To this solution was addedcupric chloride (0.16 g) and then the mixture was stirred for 8 hours atroom temperature. Precipitates were filtered off and the filtrate waswashed with a saturated sodium bicarbonate aqueous solution and thenwith water and thereafter dried over magnesium sulfate. The crystalsobtained by distilling off the solvent were washed with ether to give2,2,2-trichloroethyl2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.45g), mp 108° to 109° C.

Infrared Absorption Spectrum (Nujol) 3300, 1785, 1763, 1656 cm⁻¹.

EXAMPLE 3

2,2,2-Trichloroethyl2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(0.63 g) was dissolved in acetonitrile (12 ml). To this solution wasadded mercuric chloride (0.44 g) and then the mixture was stirred for 24hours at room temperature. After the reaction, precipitates werefiltered off and the filtrate was concentrated under reduced pressureand the obtained residue was dissolved in ethyl acetate. The ethylacetate layer was washed with water, dried and the solvent was distilledoff. The obtained residue was purified by chromatography on silica gelto give colorless needles of 2,2,2-trichloroethyl2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (190mg), mp 104° to 105° C., from the third and fourth fractions offractions each of which was separated into 50 ml.

Infrared Absorption Spectrum (Nujol) 3300, 1785, 1763, 1656 cm⁻¹.

EXAMPLE 4

To a solution of methyl2-oxo-3-(2-phenoxy-acetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate(0.12 g), in dried methylene chloride (5 ml) was added 5% methanolichydrochloric acid (0.8 ml) and the mixture was stirred for 10 hours atroom temperature. After the reaction, methylene chloride was distilledoff under reduced pressure from the reaction mixture. The residue wasextracted with ethyl acetate and the extract was washed with water anddried. The solvent was distilled off to give oily methyl2-chloromethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate(0.085 g).

Infrared Absorption Spectrum (Chloroform) 3400, 1790, 1760, 1680 cm⁻¹.

EXAMPLE 5

There was obtained oily methyl2-chloromethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate (0.36g) by treating in the similar manner as described in Example 4 usingmethyl2-oxo-3-(2-phenoxyacetamido)-4-propylaminothio-α-isopropenyl-1-azetidineacetate(0.43 g).

The following compounds were obtained by using the same procedures asthose of the Example

(1) 2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate mp to90° to 93° C. (dec.).

(2) 2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-[N-(2,2,2-trichloroethoxy)-carbonylphenylglycyl]aminopenam-3-carboxylate(powder)

(3) 2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate(gummy).

(4) 1-Cyclopropylethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (oil).

(5) 2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-[2-(sydnon-3-yl)acetamido]penam-3-carboxylate(amorphous).

(6) 2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-[2-(4-hydroxyphenyl)-2-(1-cyclopropylethoxy)carbonyl-aminoacetamido]penam-3-carboxylate(powder).

(7) 2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-[2-(2-thienyl)acetamido]-penam-3-carboxylate(oil).

(8)3,5-Di-tert.-butyl-4-hydroxybenzyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(white crystalline powder).

(9) 2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)-carbonylphenylglycyl]aminopenam-3-carboxylate(mp 130° to 135° C.).

(10) 2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-(2-cyanoacetamido)-penam-3-carboxylate(amorphous). ##STR4##

EXAMPLE 1

2,2,2-Trichloroethyl2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenylazetidine-1-acetate(0.63 g) was dissolved in acetonitrile (12 ml). To this solution wasadded mercuric chloride (0.44 g) and the mixture was stirred for 24hours at room temperature. After the reaction, precipitates werefiltered off and the filtrate was concentrated under reduced pressure.The obtained residue was dissolved in ethyl acetate and the ethylacetate layer was washed with water and then dried. The solvent wasdistilled off and the obtained residue was purified by columnchromatography on silica gel to give powdery 2,2,2-trichloroethyl3-chloro-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (70 mg) fromthe fifth and sixth fractions of fractions each of which was separatedinto 50 ml.

Infrared Absorption Spectrum (Nujol) 3400, 1775, 1760, 1675 cm⁻¹.

EXAMPLE 2

2,2,2-Trichloroethyl2-oxo-3-(2-phenyl-acetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenylazetidine-1-acetate(1.26 g) was dissolved in methylene chloride (15 ml). To this solutionwas added dried zinc chloride (0.40 g) and the mixture was stirred for 2days at room temperature. After the reaction, the reaction mixture wasfiltered and the filtrate was washed with sodium bicarbonate aqueoussolution and then with water. The residue was subjected to columnchromatography on silica gel (20 g) and eluted with chloroform. Thethird fraction of the fractions each of which was separated in about 30ml was separated and the solvent was distilled off to give powdery2,2,2-trichloroethyl3-chloro-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate.

EXAMPLE 3

Methyl2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenylazetidine-1-acetate(0.12 g) was dissolved in dry methylene chloride (5 ml). To thissolution was added 5% methanolic hydrochloric acid (0.8 ml) and themixture was stirred for 10 hours at room temperature. After thereaction, the reaction mixture was concentrated under reduced pressureand the residue was extracted with ethyl acetate. The extract was washedwith water and dried. The solvent was distilled off and the residue wassubjected to column chromatography on silica gel using chloroform asdeveloping solvent to give oily methyl3-chloro-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (0.07 g).

Infrared Absorption Spectrum (Chloroform) 3410, 1775, 1742, 1690 cm⁻¹.

EXAMPLE 4

Methyl2-oxo-3-(2-phenoxyacetamido)-4-propylaminothio-α-isopropenylazetidine-1-acetate(0.43 g) was dissolved in dried methylene chloride. To this solution wasadded 5% methanolic hydrochloric acid (2 ml) and the mixture was stirredfor 10 hours at room temperature. After the reaction, the reactionmixture was concentrated under reduced pressure and the residue wasextracted with ethyl acetate. The extract was washed with water anddried. The solvent was distilled off and the residue was subjected tocolumn chromatography on silica gel using chloroform as developingsolvent to give oily methyl3-chloro-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (310 mg).

The following compounds were obtained by using the same procedures asthose of the Examples 1 to 4.

    __________________________________________________________________________     ##STR5##                                                                                                      Property of                                  No.                                                                                R.sup.1       R.sup.2                                                                               R.sup.3                                                                           Z the product                                  __________________________________________________________________________        ##STR6##     COOCH.sub.3                                                                            CH.sub.3                                                                          Br amorphous                                    2                                                                                 ##STR7##     COOCH.sub.3                                                                            CH.sub.3                                                                          I  oil                                          3                                                                                 ##STR8##     COOH     CH.sub.3                                                                          Br amorphous                                    4                                                                                 ##STR9##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          Br mp 90° to 93° C. (dec.)        5  NCCH.sub.2 CONH                                                                             COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          Br amorphous                                    6                                                                                 ##STR10##    COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          Br oil                                          __________________________________________________________________________     ##STR11##

EXAMPLE 1

Methyl2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidine-acetate(1.06 g) and silver acetate (0.34 g) were suspended in tert-butanol andthe mixture was refluxed for 48 hours. After the reaction, precipitateswere filtered off and the filtrate was concentrated under reducedpressure. The residue was extracted with ethyl acetate. The ethylacetate layer was washed with water, dried and the solvent was distilledoff. The obtained residue was purified by column chromatography onsilica gel using chloroform as developing solvent to give pale yellowoil of methyl2-acetoxymethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate (490mg).

Infrared Absorption Spectrum (CHCl₃) 3410, 1792, 1745, 1740, 1690 cm⁻¹.

EXAMPLE 2

2,2,2-Trichloroethyl2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidine-acetate(0.63 g) was dissolved in chloroform (10 ml). To this solution was addedlead tetraacetate (1.77 g) and the mixture was refluxed for 24 hours. Tothe reaction mixture was added water and precipitates were filtered off.The filtrate was separated into chloroform layer and aqueous layer andthe aqueous layer was extracted with chloroform. The chloroform layerwas combined, dried over magnesium sulfate and then the solvent wasdistilled off. The residue was purified by column chromatography onsilica gel using chloroform as developing solvent to give2,2,2-trichloroethyl2-acetoxymethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.11g), mp 122° to 123° C.

EXAMPLE 3

2,2,2-Trichloroethyl2-oxo-6-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(1.26 g) was dissolved in a mixture of chloroform (10 ml) and aceticacid (10 ml). To this solution was added lead tetraacetate (1.80 g) andthe mixture was stirred for 7 hours at room temperature. Leadtetraacetate (1.80 g) was further added to this solution and thesolution was stirred for 8 hours at 50° C. To the reaction mixture wasadded chloroform, and the solution was washed with a saturated sodiumbicarbonate aqueous solution and then with water and thereafter driedover magnesium sulfate. The residue obtained by distilling off thesolvent was purified by column chromatography on silica gel usingchloroform as developing solvent to give 2,2,2-trichloroethyl2-acetoxymethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.26g).

Infrared Absorption Spectrum (Nujol) 3280, 1792, 1748, 1660 cm⁻¹.

EXAMPLE 4

2,2,2-Trichloroethyl2-oxo-3-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]-amino-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetideacetate(1.52 g) was dissolved in dry methylene chloride (15 ml) underice-cooling. To this solution was dropwise added a solution ofthiocyanogen (1 m mole) in methylene chloride (10 ml) and the mixturewas stirred for 24 hours at the same temperature. Precipitates wasfiltered off and the filtrate was washed with a saturated sodiumbicarbonate aqueous solution and then with water. After drying overmagnesium sulfate, the solvent was distilled off under reduced pressureto give oily 2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate(1.3 g).

Infrared Absorption Spectrum (Film) 1780, 1765, 1680 cm⁻¹.

EXAMPLE 5

2,2,2-Trichloroethyl2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(0.63 g) was dissolved in dried methylene chloride (10 ml) underice-cooling. To this solution was dropwise added a solution ofthiocyanogen (0.6 m mole) in methylene chloride (5 ml). After themixture was stirred for 24 hours at the same temperature, precipitateswere filtered off. The filtrate was concentrated under reduced pressureand the residue was dissolved in ethyl acetate (10 ml). The ethylacetate layer was washed with a saturated sodium bicarbonate aqueoussolution and then with water and thereafter dried over magnesiumsulfate. After the solvent was distilled off, the residue wascrystallized by adding a small amount of ether. The crystals werefiltered off and the filtrate was concentrated to give oily2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl6-(2-phenoxyacetamido)penam-3-carboxylate(0.49 g).

Infrared Absorption Spectrum (Film) 1785, 1760, 1690 cm⁻¹.

EXAMPLE 6

2,2,2-Trichloroethyl2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(5.04 g) was dissolved in dried methylene chloride (20 ml). To thissolution was dropwise added a solution of thiocyanogen (4.5 m mole) inmethylene chloride for 5 minutes under ice-cooling. After stirring for 7hours at the same temperature, precipitates were filtered off. Thefiltrate was washed with a saturated sodium bicarbonate aqueous solutionand then with water and thereafter dried over magnesium sulfate. Afterdistilling off the solvent under reduced pressure, the residue wascrystallized by adding a small amount of ether to give2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(3.58 g), mp 137° to 140° C.

EXAMPLE 7

2,2,2-Trichloroethyl2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(0.63 g) and potassium thiocyanate (150 mg) were dissolved in driedacetone (10 ml). To this solution was added p-toluenesulfonic acidmonohydrate (0.19 g) and the mixture was stirred for 24 hours at roomtemperature. Precipitates were filtered off and the filtrate wasconcentrated under reduced pressure and then the residue was dissolvedin ethyl acetate. The ethyl acetate layer was washed with a saturatedsodium bicarbonate aqueous solution and then with water and thereafterdried over magnesium sulfate. The residue obtained by distilling off thesolvent was crystallized by adding a small amount of ether to give2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(330 mg).

EXAMPLE 8

2,2,2-Trichloroethyl2-oxo-3-[3-(2-chlorophenyl)-5-methyl-isoxazol-4-carboxamido]-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(0.70 g) was dissolved in dried methylene chloride (10 ml) underice-cooling. To this solution was dropwise added a solution ofthiocyanogen (0.5 m mole) in methylene chloride (5 ml) and the mixturewas stirred for 24 hours at the same temperature. Precipitates werefiltered off and the filtrate was washed with a saturated sodiumbicarbonate aqueous solution and then with water and thereafter dried.The solvent was distilled off and the residue was pulverized by addingpetroleum ether (about 10 ml) to give 2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carboxamido]-penam-3-carboxylate(500 mg).

Infrared Absorption Spectrum (Nujol) 1785, 1770, 1670 cm⁻¹.

EXAMPLE 9

Acetic acid (5 ml) was added to a solution of 2,2,2-trichloroethyl2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(1.26 g) in ethyl acetate (15 ml) To this solution was added silveracetate (0.68 g) under stirring at room temperature and the mixture wasstirred for 4 hours at the same temperature. After the reaction,precipitates were filtered off from the reaction mixture and thefiltrate was washed with water, with 5% sodium bicarbonate aqueoussolution and then filtered. The filtrate was washed with water, driedand the solvent was distilled off. The oily residue (0.87 g) waspurified by thin layer chromatography and recrystallized from ether togive colorless needles of 2,2,2-trichloroethyl2-acetoxymethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate, mp116° to 118° C.

EXAMPLE 10

Methyl2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate(454 g) was dissolved in methylene chloride (20 ml). To this solutionwere added methanol (5 ml) and then boron trifluoride etherate (0.124 g)under cooling at 0° C. The mixture was stirred for 3 hours at the sametemperature and further stirred for 2 hours to 5° to 10° C. After thereaction, the reaction mixture was washed with 5% sodium bicarbonateaqueous solution and then with water, dried and the solvent wasdistilled off. The oily residue (25 g) was subjected to columnchromatography on silica gel and eluted with chloroform. The eluate wasseparated into each 50 ml fraction and the seventh and eighth fractionswere combined. The solvent was distilled off to give oily methyl2-methoxymethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate.

Infrared Absorption Spectrum (CHCl₃) 3370, 1787, 1742, 1685 cm⁻¹.

    __________________________________________________________________________     ##STR12##                                                                    No.                                                                                R.sup.1        R.sup.2                                                                               R.sup.3                                                                           Y          Property of the                    __________________________________________________________________________                                               product                                ##STR13##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          N.sub.3     mp 105° to 106°                                                 C.                                 2                                                                                 ##STR14##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR15##  Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3320,                                                   1790, 1765, 1680 cm.sup.-1.        3                                                                                 ##STR16##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR17##  Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3400,                                                   1790, 1765, 1680 cm.sup.-1.        4                                                                                 ##STR18##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR19##  Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3300,                                                   1790, 1765, 1680 cm.sup.-1.        5                                                                                 ##STR20##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          SOOCH.sub.3 Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3390,                                                   1790, 1765, 1680-1690                                                         cm.sup.-1.                         6                                                                                 ##STR21##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR22##  Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3300,                                                   1788, 1764, 1675 cm.sup.-1         7                                                                                 ##STR23##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR24##  Oil Infrared                                                                  AbsorptionSpectrum                                                            (CHCl.sub.3) 3200, 1790, 1770,                                                1678 cm.sup.-1                     8                                                                                 ##STR25##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR26##  Oil Infrared Absorption                                                       Spectrum (Film) 3250, 1780,                                                   1765, 1665 cm.sup.-1               9                                                                                 ##STR27##     COOCH.sub.3                                                                            CH.sub.3                                                                           ##STR28##  Infrared Absorption Spectrum                                                  (Film) 3300, 1785, 1745, 1690                                                 cm.sup.-1                          10                                                                                ##STR29##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR30##  Oil Infrared Absorption                                                       Spectrum (Film) 3270, 1780,                                                   1760, 1710, 1680 cm.sup.-1         11                                                                                ##STR31##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR32##  Oil Infrared Absorption                                                       Spectrum (Film) 3270, 1760,                                                   1710, 1680 cm.sup.-1               12                                                                                ##STR33##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          OCH.sub.3   Oil  Infrared Absorption                                                      Spectrum (CHCl.sub.3) 3360,                                                   1785, 1757, 1666 cm.sup.-1         13                                                                                ##STR34##     COOCH.sub.3                                                                            CH.sub.3                                                                           ##STR35##  Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3410,                                                   1785, 1748, 1690 cm.sup.-1         14                                                                                ##STR36##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR37##  Amorphous Infrared Absorption                                                 Spectrum (Nujol) 3220, 1780,                                                  1760, 1700 cm.sup.-1               15                                                                                ##STR38##     COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR39##  Amorphous Infrared Absorption                                                 Spectrum (Nujol) 3300, 1780,                                                  1770, 1665 cm.sup.-1               16 H.sub.2 N      COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          SCN         toluenesulfonate                                                              mp 182° to 185°                                                 C. (dec. )                         17                                                                                ##STR40##     COOH     CH.sub.3                                                                          SOOCH.sub.3 N, N'-dibenzylethylenediamine                                                 salt mp 105° to                                                        107° C.                     18                                                                                ##STR41##     COOH     CH.sub.3                                                                           ##STR42##  N,N'-dibenzylethylenediamine                                                  salt mp 100° C. (dec.)      19                                                                                ##STR43##     COOH     CH.sub.3                                                                           ##STR44##  mp 120° C.                  20                                                                                ##STR45##     COOH     CH.sub.3                                                                           ##STR46##  N,N'-dibenzylethylenediamine                                                  salt mp 117° to                                                        119° C. (dec.)              21                                                                                ##STR47##     COOH     CH.sub.3                                                                           ##STR48##  mp 152° to 154°                                                 C.                                 22                                                                                ##STR49##     COOH     CH.sub.3                                                                           ##STR50##  N,N'-dibenzylethylenediamine                                                  salt mp 150° to                                                        152° C. (dec.)              23                                                                                ##STR51##     COOH     CH.sub.3                                                                           ##STR52##  Sodium salt  mp 200°                                                   C. (dec.)                          24                                                                                ##STR53##     COOH     CH.sub.3                                                                           ##STR54##  Sodium salt mp 185° to                                                 186° C.                     __________________________________________________________________________                                               (dec.)                              ##STR55##

EXAMPLE 1

Potassium thiocyanate (1.17 g) was dissolved in a mixture of water (20ml) and acetone (100 ml). To this solution was added2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenyl-acetamido)penam-3carboxylate (5.45 g)at room temperature and the mixture was stirred for 5.5 hours at roomtemperature. After removing acetone under reduced pressure at roomtemperature, precipitates were collected by filtration, washed withwater and further washed with ethanol to give 2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(4.10 g). This substance was recrystallized from isopropylethercontaining 5% acetone to give pure compound, mp 133° to 135° C.

Analysis for C₁₉ H₁₈ N₃ O₄ S₂ Cl₃ Calc'd. C 43.64, H 3.47, N 8.04, S12.27, Cl 20.34 Found: C 43.84, H 3.26, N 7.99, S 12.31, Cl 20.31.

EXAMPLE 2

A mixture of 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.08g), sodium azide (0.26 g), acetone (20 ml) and water (4 ml) was stirredfor 4 hours at room temperature. After removing acetone under reducedpressure, the residue was extracted with ethyl acetate. The ethylacetate layer was washed with water, with a saturated sodium bicarbonatequeous solution and further with water and then dried over magnesiumsulfate. The solvent was distilled off under reduced pressure and asmall amount of ether was added to the residue. Precipitated crystalswere filtered off and the solvent was distilled off from the filtrate.The crystalline residue was purified by column chromatography on silicagel using chloroform as developing solvent to give 2,2,2-trichloroethyl2-azidomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (150mg). This substance was crystallized by adding a small amount of amixture of ether and petroleum ether and the crystals wererecrystallized from ether to give pure compound, mp 105° to 106° C.

Analysis for C₁₈ H₁₈ N₅ O₄ SCl₃ Calc'd: C 42.66, H 3.58, N 13.82, S6.33, Cl 20.99. Found: C 42.66, H 3.40, N 13.69, S 6.79, Cl 20.74.

EXAMPLE 3

5-Methyl-1,3,4-thiadiazole-2-thiol (0.16 g) was dissolved in a mixtureof pH 6.5 phosphate buffer (5 ml) and acetone (10 ml). To this solutionwas added 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g)and the mixture was stirred for 3 hours at room temperature. Thereaction mixture was concentrated under reduced pressure and acetone wasdistilled off and thereafter the residue was extracted with ethylacetate. The ethyl acetate layer was washed with sodium bicarbonateaqueous solution and then with water and thereafter dried over magnesiumsulfate. The solvent was distilled off and the residue was purified bycolumn chromatography on silica gel using chloroform as developingsolvent to give oily 2,2,2-trichloroethyl2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate(0.09 g) from the second and third fractions each of which was separatedinto about 30 ml.

Infrared Absorption Spectrum (CHCl₃) 3320, 1790, 1765, 1680 cm⁻¹.

EXAMPLE 4

5-Methyl-1,3,4-thiadiazole-2-thiol (0.20 g) and sodium bicarbonate (0.85g) were dissolved in formamide (7 ml). To this solution was added2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.54g), and the mixture was stirred for 5 hours at room temperature. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed a saturated sodiumbicarbonate aqueous solution and then with water and thereafter driedover magnesium sulfate. The residue obtained by distilling off thesolvent was purified by column chromatography on silica gel usingchloroform as developing solvent to give oily 2,2,2-trichloroethyl2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.20 g) from the third fraction of fractions each of which wasseparated into about 30 ml.

EXAMPLE 5

Benzothiazole-2-thiol (0.20 g) was dissolved in a mixture of pH 6.7phosphate buffer (15 ml) and dioxane (15 ml). To this solution was added2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g)and the mixture was stirred for 7 hours at room temperature. After thereaction was completed, dioxane was distilled off and the residue wasextracted with ethyl acetate. The ethyl acetate layer was washed with a2% potassium carbonate aqueous solution and then with water andthereafter dried over magnesium sulfate. The residue obtained bydistilling off the solvent was purified by column chromatography onsilica gel using chloroform as developing solvent to give oily2,2,2-trichloroethyl2-(benzothiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.15 g) from the second fraction of fractions each of which wasseparated into 30 ml.

Infrared Absorption Spectrum (CHCl₃). 3400, 1790, 1765, 1680 cm⁻¹.

EXAMPLE 6

To a solution of 1-methyl-1H-tetrazole-5-thiol (0.23 g) in a mixture ofpH 6.9 phosphate buffer (15 ml) and acetone (20 ml) was added2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54g), and the mixture was stirred for 5 hours at room temperature. Acetonewas distilled off from the reaction mixture. The aqueous layer wasextracted with ethyl acetate and the extract was washed with sodiumbicarbonate aqueous solution and then with a saturated sodium chlorideaqueous solution. After the extract was dried over magnesium sulfate,the solvent was distilled off. The residue was purified by columnchromatography on silica gel to give oily2,2,2-trichloroethyl-2-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.27 g).

Infrared Absorption Spectrum (CHCl₃). 3300, 1790, 1765, 1680 cm⁻¹.

EXAMPLE 7

Acetone (20 ml) and thioacetic acid (0.12 g) were added to pH 6.7phosphate buffer (20 ml). To a mixture was added 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g)under stirring. After stirring for 5 hours at room temperature, thereaction mixture was post-treated in the similar manner as described inExample 6 to give oily 2,2,2-trichloroethyl2-acetylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.173 g).

Infrared Absorption Spectrum (CHCl₃) 3390, 1790, 1965, 1690-1685 cm⁻¹.

EXAMPLE 8

Sodium piperidine-1-dithiocarboxylate (0.37 g) was dissolved in amixture of pH 6.7 phosphate buffer (20 ml) and acetone (25 ml) and thento this solution was added 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54g). After stirring for 3 hours at room temperature, the reaction mixturewas post-treated in the similar manner as described in Example 6 to giveoily 2,2,2-trichloroethyl2-piperidinothiocarbonyl-thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.11 g).

Infrared Absorption Spectrum (CHCl₃) 3300, 1788, 1764, 1675 cm⁻¹.

EXAMPLE 9

Acetone (25 ml) was added to a solution of 1-methylimidazole-2-thiol(0.23 g) in pH 6.9 phosphate buffer (20 ml). To this solution was added2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54g), and the mixture was stirred for 3 hours at room temperature.

The reaction mixture was post-treated in the similar manner as describedin Example 6 to give oily 2,2,2-trichloroethyl2-(1-methylimidazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.29 g).

Infrared Absorption Spectrum (CHCl₃) 3200, 1790, 1770, 1678 cm⁻¹.

EXAMPLE 10

Acetone (25 ml) was added to a solution of pyridine-4-thiol (0.22 g) inpH 6.8 phosphate buffer (20 ml). To this solution was added2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54g), and the mixture was stirred for 3 hours at room temperature.

The reaction mixture was post-treated in the similar manner as describedin Example 6 to give oily 2,2,2-trichloroethyl2-(4-pyridyl)-thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.15 g).

Infrared Absorption Spectrum (Film) 3250, 1780, 1765, 1665 cm⁻¹.

EXAMPLE 11

5-Methyl-1,3,4-thiadiazole-2-thiol (0.4 g) was dissolved in a mixture ofpH 7.3 phosphate buffer (20 ml) and acetone (20 ml). To this solutionwas added a solution of methyl2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.80g) in acetone (10 ml) and the mixture was stirred for 4 hours at roomtemperature. After the reaction was completed, acetone was distilled offfrom the reaction mixture and the residue was extracted with ethylacetate. The extract was washed with sodium bicarbonate aqueous solutionand then with water and thereafter dried over magnesium sulfate. Thesolvent was distilled off and the residue was subjected to columnchromatography on silica gel (60 g) and eluted with chloroform. Theeluate was separated into fractions of each about 30 ml to give methyl2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate(0.28 g) from the fourth to seventh fractions.

Infrared Absorption Spectrum (Film) 3300, 1785, 1745, 1690 cm⁻¹.

EXAMPLE 12

Acetic acid (2 ml) was added to a solution of 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamide)penam-3-carboxylate (0.54 g)in methylene chloride (10 ml). And to this solution was added silveracetate (0.34 g) under stirring at room temperature and then the mixturewas stirred for 2.5 hours. After the reaction was completed, thereaction mixture was filtered under reduced pressure and the filtratewas washed with 5% hydrochloric acid and then filtered again. The oilyresidue was crystallized by treating with ether and the crystals werecollected by filtration and then dried to give colorless needles of2,2,2-trichloroethyl2-acetoxymethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylic (0.21g), mp 116° to 118° C.

EXAMPLE 13

A solution of 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]-aminopenam-3-carboxylate(6.75 g) in acetone (50 ml) was added to a solution of1-methyl-1H-tetrazole-5-thiol (2.6 g) in a mixture of phosphate buffer(200 ml) and acetone (200 ml), under cooling at 5° C., and the mixturewas stirred for 5 hours at the same temperature. After the reaction wascompleted, acetone was distilled off from the reaction mixture underreduced pressure and the residue was extracted with ethyl acetate. Theextract was washed with 5% sodium bicarbonate aqueous solution and thenwith water, dried. The solvent was distilled off. The oily residue wassubjected to column chromatography on silica gel (180 g) and eluted withchloroform. The eluate was separated into fractions of each 50 ml andafter collecting the fractions of the eleventh to sixteenth, the solventwas distilled off to give oily 2,2,2-trichloroethyl2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate (3.15 g).

Infrared Absorption Spectrum (Film) 3270, 1780, 1760, 1710, 1680 cm⁻¹.

EXAMPLE 14

By treating in the similar manner as described in Example 13 using2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate(6.72 g), 5-methyl-1,3,4-thiadiazole-2-thiol (1.98 g), pH 6.8 phosphatebuffer (200 ml) and acetone (250 ml), there was obtained oily2,2,2-trichloroethyl2-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate(1.16 g).

Infrared Absorption Spectrum (CHCl₃) 3420, 1790, 1770, 1708, 1687 cm⁻¹.

EXAMPLE 15

A solution of 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate(3.6 g) in formamide (40 ml) was added to a solution of sodiumbicarbonate (0.66 g) and 5-methyl-1,3,4-thiadiazole-2-thiol (1.1 g) informamide (60 ml) under ice-cooling, after which the mixture was stirredfor 4.5 hours at the same temperature. After the reaction was completed,the reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with 5% sodium bicarbonate aqueoussolution and then with water, dried, after which the solvent wasdistilled off. The oily residue was subjected to column chromatographyon silica gel (110 g) and eluted with chloroform. The eluate wasseparated into fractions of each 50 ml and after collecting thefractions of the fifteenth and sixteenth, the solvent was distilled offto give oily2,2,2-trichloroethyl2-(5-methyl-1,3,-thiadiazol-2-yl)thiomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate(0.42 g).

EXAMPLE 16

2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.10 g)dissolved in methylene chloride (15 ml). To this solution was addedaniline (0.28 g) under cooling at -10° C. and then silver fluoroborate(0.43 g), after which the mixture was stirred for 2 hours. After thereaction was completed, the reaction mixture was washed with a dilutephosphoric acid aqueous solution and then with water, dried overmagnesium sulfate, after which the solvent was distilled off. Theresidue was subjected to column chromatography on silica gel (20 g) andeluted with chloroform. The eluate was separated into fractions of eachabout 20 ml. The second to seventh fractions were collected and thesolvent was distilled off to give 2,2,2-trichloroethyl2-anilinomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.84g), mp 148° to 149° C.

Infrared Absorption Spectrum (CHCl₃) 3400, 1780, 1765, 1680 cm⁻¹.

EXAMPLE 17

By treating in the similar manner as described in Example 16 usingmethyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate(0.88 g), aniline (0.28 g), silver fluoroborate (0.43 g) and methylenechloride (15 ml), there was obtained oily methyl2-anilinomethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate(0.41 g) from the fractions of the third to seventh.

Infrared Absorption Spectrum (CHCl₃) 3410, 1785, 1748, 1690 cm⁻¹.

EXAMPLE 18

2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (1.10g) was dissolved in methylene chloride (12 ml) and to this solution wasadded methanol (3 ml). And to the solution was added silver fluoroborate(0.45 g) under stirring under cooling at -10° C. and the mixture wasstirred for 2 hours at the same temperature. After the reaction wascompleted, the reaction mixture was filtered and the filtrate was washedwith sodium bicarbonate aqueous solution and then with water, dried overmagnesium sulfate and thereafter concentrated. The residue was subjectedto column chromatography on silica gel (25 g) and eluted withchloroform. The eluate was separated into fractions of about 20 ml andthe first and second fractions were collected. After distilling off thesolvent, the residue was dried to give oily 2,2,2-trichloroethyl2-methoxymethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate.

Infrared Absorption Spectrum (CHCl₃) 3360, 1785, 1757, 1666 cm⁻¹.

EXAMPLE 19

By treating in the similar manner as described in Example 18 usingmethyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylateinstead of 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate, therewas obtained oily methyl2-methoxymethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate.

Infrared Absorption Spectrum (CHCl₃) 3370, 1787, 1742, 1685 cm⁻¹.

EXAMPLE 20

By treating in the similar manner as described in Example 11 using2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylateand 1-methyl-1H-tetrazole-5-thiol in a mixture of pH 6.85 phosphatebuffer and acetone, there was obtained amorphous 2,2,2-trichloroethyl2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate.

Infrared Absorption Spectrum (Nujol) 3300, 1780, 1770, 1665 cm⁻¹.

EXAMPLE 21

By treating in the similar manner as described in Example 11 using2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)-acetamido]penam-3-carboxylateand 1-methyl-1H-tetrazole-5-thiol in a mixture of pH 6.85 phosphatebuffer and acetone, there was obtained amorphous 2,2,2-trichloroethyl2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)acetamido]penam-3-carboxylate.

Infrared Absorption Spectrum (Nujol) 3220, 1780, 1760, 1700 cm⁻¹.

The following compounds were obtained by using the same procedures asthose of the Example 1 to 21.

    __________________________________________________________________________     ##STR56##                                                                    No.                                                                              R.sup.1          R.sup.2  R.sup.3                                                                           Y          Property of the                   __________________________________________________________________________                                                Products                              ##STR57##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          SCN        Oil Infrared Absorption                                                       Spectrum (File) 1785, 1760,                                                   1690 cm.sup.-1.                   2                                                                                 ##STR58##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          SCN        Oil Infrared Absorption                                                       Spectrum (File) 1780, 1765,                                                   1680 cm.sup.-1.                   3                                                                                 ##STR59##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          SCN        Powder Infrared Absorption                                                    Spectrum (Nujol) 1785, 1770,                                                  1670 cm.sup.-1.                   4  H.sub.2 N        COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          SCN        toluenesulfanate                                                              up 182° to 185°                                                 C. (dec.)                         5                                                                                 ##STR60##       COOH     CH.sub.3                                                                          SCOCH.sub.3                                                                              N,N'-dibenzylethylenediamine                                                  salt mp 105° to                                                        107° C.                    6                                                                                 ##STR61##       COOH     CH.sub.3                                                                           ##STR62## N,N'-dibenzylethylenediamine                                                  salt mp 100° C.                                                        (dec.)                            7                                                                                 ##STR63##       COOH     CH.sub.3                                                                           ##STR64## mp 120° C.                 8                                                                                 ##STR65##       COOH     CH.sub.3                                                                           ##STR66## N,N'-dibenzylethylenediamine                                                  salt mp 117° to                                                        119° C.(dec.)              9                                                                                 ##STR67##       COOH     CH.sub.3                                                                           ##STR68## mp 152° to 154°                                                 C.                                10                                                                                ##STR69##       COOH     CH.sub.3                                                                           ##STR70## N,N'-dibenzylethylenediamine                                                  salt mp 150° to                                                        152° (dec.)                11                                                                                ##STR71##       COOH     CH.sub.3                                                                           ##STR72## Sodium salt mp 200° C.                                                 (dec.)                            12                                                                                ##STR73##       COOH     CH.sub.3                                                                           ##STR74## Sodium salt mp 185° to                                                 186° C.                    __________________________________________________________________________                                                (dec.)                             ##STR75##

EXAMPLE 1

2,2,2-Trichloroethyl3-bromo-3-methyl-7-(2-phenylacetamido)cepham---carboxylate (1.10 g) wasdissolved in methylene chloride (15 ml) and to this solution was addedaniline (0.28 g). And to the solution was added silver fluoroborate(0.45 g) under stirring under ice-cooling and the mixture was stirredfor 4 hours at the same temperature. After the reaction was completed,the reaction mixture was filtered. The filtrate was washed with a diluteaqueour solution of phosphoric acid and then with water, dried overmagnesium sulfate and concentrated. The residue was subjected to columnchromatography on silica gel (25 g) and eluted with chloroform. Theeluate was separated into fractions of each about 20 ml and the secondto eighth fractions were collected and then the solvent was distilledoff to give 2,2,2-trichloroethyl2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54g), mp 148° to 149° C.

Infrared Absorption Spectrum (CHCl₃) 3400, 1780, 1765, 1680 cm⁻¹.

The following compounds were obtained by using the same procedure asthat of the Example 1.

    __________________________________________________________________________     ##STR76##                                                                    No.                                                                                R.sup.1          R.sup.2                                                                               R.sup.3                                                                           Y           Property of the                 __________________________________________________________________________                                                  product                             ##STR77##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          N.sub.3      mp 105° to                                                             106° C.                  2                                                                                 ##STR78##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR79##   Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3320,                                                   1790, 1765, 1680 cm.sup.-1      3                                                                                 ##STR80##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR81##   Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3400,                                                   1790, 1765, 1680 cm.sup.-1      4                                                                                 ##STR82##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR83##   Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3300,                                                   1790, 1765, 1680 cm.sup.-1      5                                                                                 ##STR84##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          SCOCH.sub.3  Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3390,                                                   1790, 1765, 1690-1680                                                         cm.sup.-1                       6                                                                                 ##STR85##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR86##   Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3300,                                                   1788, 1764, 1675 cm.sup.-1      7                                                                                 ##STR87##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR88##   Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3200,                                                   1790, 1770, 1678 cm.sup.-1      8                                                                                 ##STR89##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR90##   Oil Infrared Absorption                                                       Spectrum (Film) 3250, 1780,                                                   1765, 1665 cm.sup.-1            9                                                                                 ##STR91##       COOCH.sub.3                                                                            CH.sub.3                                                                           ##STR92##   Infrared Absorption                                                           Spectrum (Film) 3300, 1785,                                                   1745, 1690 cm.sup.-1            10                                                                                ##STR93##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR94##   Oil Infrared Absorption                                                       Spectrum (Film) 3270, 1780,                                                   1760, 1710, 1680 cm.sup.-1      11                                                                                ##STR95##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR96##   Oil Infrared Absorption                                                       Spectrum (Film) 3270, 1760,                                                   1710, 1680 cm.sup.-1            12                                                                                ##STR97##       COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          OCH.sub.3    Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3360,                                                   1785, 1757,  1666                                                             cm.sup.-1                       13                                                                                ##STR98##       COOCH.sub.3                                                                            CH.sub.3                                                                           ##STR99##   Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3410,                                                   1785, 1748,  1690                                                             cm.sup.-1                       14                                                                                ##STR100##      COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR101##  Amorphous Infrared                                                            Absorption Spectrum (Nujol)                                                   3220, 1780, 1760, 1700                                                        cm.sup.-1                       15                                                                                ##STR102##      COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR103##  Amorphous Infrared                                                            Absorption Spectrum (Nujol)                                                   3300, 1780, 1770, 1665                                                        cm.sup.-1                       16                                                                                ##STR104##      COOCH.sub.3                                                                            CH.sub. 3                                                                         OCH.sub.3    Oil Infrared Absorption                                                       Spectrum (CHCl.sub.3) 3370,                                                   1787, 1742, 1685 cm.sup.-1      17                                                                                ##STR105##      COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          SCH          Oil Infrared Absorption                                                       Spectrum (Film) 1785, 1760,                                                   1690 cm.sup.-1                  18                                                                                ##STR106##      COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          SCN          Oil Infrared Absorption                                                       Spectrum (Film) 1780, 1765,                                                   1680 cm.sup.-1                  19                                                                                ##STR107##      COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          SCN          Powder Infrared Absorption                                                    Spectrum (Nujol) 1785,                                                        1770, 1670 cm.sup.-1            20                                                                                ##STR108##      COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          SCN          mp 137° to                                                             140° C.                  21 H.sub.2 N         COOCH.sub.2 CCl.sub.3                                                                 CH.sub.3                                                                          SCN          toluenesulfonate mp                                                           182° to 185°                                                    C. (dec.)                       22                                                                                ##STR109##      COOH     CH.sub.3                                                                          SCOCH.sub.3  N,N'-dibenzylethylenediamine                                                   salt mp 105° to                                                       107° C.                  23                                                                                ##STR110##      COOH     CH.sub.3                                                                           ##STR111##  N,N'-dibenzylethylenediamine                                                   salt mp 100° C.                                                       (dec.)                          24                                                                                ##STR112##      COOH     CH.sub.3                                                                           ##STR113##  mp 120° C.               25                                                                                ##STR114##      COOH     CH.sub.3                                                                           ##STR115##  N,N'-dibenzylethylenediamine                                                   salt mp 117° to                                                       119° C. (dec.)           26                                                                                ##STR116##      COOH     CH.sub.3                                                                           ##STR117##  mp 152° to                                                             154° C.                  27                                                                                ##STR118##      COOH     CH.sub.3                                                                           ##STR119##  N,N'-dibenzylethylenediamine                                                   salt mp 150° to                                                       152° C. (dec.)           28                                                                                ##STR120##      COOH     CH.sub.3                                                                           ##STR121##  Sodium salt mp 200°                                                    C. (dec.)                       29                                                                                ##STR122##      COOH     CH.sub.3                                                                           ##STR123##  Sodium salt mp 185°                                                    to 186° C.               __________________________________________________________________________                                                  (dec.)                           ##STR124##

EXAMPLE 1

A solution of m-chloroperbenzoic acid (1.39 g) in chloroform (15 ml) wasadded to a solution of 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (3.74 g)in chloroform (35 ml) under ice-cooling. The mixture was stirred underice-cooling for 1 hour, and precipitates were filtered off. The filtratewas washed with a saturated sodium bicarbonate aqueous solution andwater in turn and dried over magnesium sulfate. After the solvent wasremoved under reduced pressure, the residue was crystallized by adding alittle of ether. The Crystals were filtered to give colorless crystalsof 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-β-oxide(3.15 g), mp 114°-115° C. (dec.).

Analysis C₁₈ H₁₈ O₅ N₂ SCl₃ Br Calcd. C 38.55, H 3.24, N 4.99 Found C38.40, H 3.12, N 4.68.

EXAMPLE 2

2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (540 mg)was supended in a mixed solution of pyridine (10 ml) and water (1 ml) at-35°--40° C. To the suspension was dropwise added isocyanuroyl chloride(110 mg). The mixture was stirred for an hour and twenty minutes andthen the mixture was poured into a mixed solution of 20% aqueousphosphoric acid (50 ml) and ethyl acetate (20 ml) under ice-cooling. Theethyl acetate fraction was separated. After the water layer wasextracted with ethyl acetate, the ethyl acetate extract was combinedwith the above-obtained ethyl acetate layer. The extract was washed with5% phosphoric acid, water, saturated sodium bicarbonate aqueous solutionand water in turn, and then dried over magnesium sulfate. After thesolvent was removed, the residue was subjected to column chromatographyon silica gel with chloroform. The 3rd fraction was concentrated to give2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-β-oxide(130 mg). The 5th fraction was concentrated to give 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate-1-α-oxide (170 mg).

Infrared Absorption Spectrum (CHCl₃) of the α-oxide compound: 3420,1795, 1770, 1665 cm⁻¹.

EXAMPLE 3

m-Chloroperbenzoic acid (210 mg) was dropwise added to a solution of2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(522 mg) in chloroform (10 ml) under ice-cooling. The mixture wasstirred under ice-cooling for 1 hour and the solid was filtered off. Thefiltrate was washed with a saturated sodium bicarbonate aqueous solutionand water, in turn, and then dried over magnesium sulfate. The solventwas removed to give colorless powder of 2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-.beta.-oxide(540 mg).

Infrared Absorption Spectrum (Nujol) 3330, 2130, 1797, 1778(sh.), 1677cm⁻¹.

EXAMPLE 4

2,2,2-Trichloroethyl2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(522 mg) was suspended in a mixed solution of pyridine (10 ml) and water(1 ml) at -35°--40° C. To the suspension was dropwise added isocyanuroylchloride (110 mg) at -35°--40° C. The mixture was stirred at -35°--40°C. for 1 hour, and then poured into a mixed solution of ice-cooled 20%phosphoric acid (50 ml) and ethyl acetate (20 ml), and then the ethylacetate layer was separated. After the water layer was extracted withethyl acetate, the extract was combined with the above-obtained ethylacetate layer. The extract was washed with 5% phosphoric acid, water,saturated sodium bicarbonate aqueous solution and water, in turn, anddried over magnesium sulfate. After the solvent was distilled off, theresidue was purified by column chromatography on silica gel withchloroform to give 2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-β-oxide (140 mg).

EXAMPLE 5

2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(522 mg) was suspended in a mixed solution of pyridine (12 ml) and water(12 ml) at -25°--35° C. To the suspension was added phenyliododichloride(550 mg). And the mixture was stirred at -25°--35° C. for 3 hours,phenyliododichloride (550 mg) was further added to the mixture. Afterstirring for 1 hour, phenyliododichloride (550 mg) was added to themixture again. The reaction mixture was stirred for additional one hour,poured into a mixed solution of 20% phosphoric acid (50 ml) and ethylacetate (20 ml), and then the ethyl acetate layer was separated. Theaqueous layer was extracted with ethyl acetate, which was combined withthe above-obtained ethyl acetate layer. The combined ethyl acetate layerwas washed with 5% phosphoric acid, water, saturated sodium bicarbonateaqueous solution and water, in turn, and then dried over magnesiumsulfate. After the solvent was removed under reduced pressure, theresidue was subjected to column chromatography on silica gel with amixed solution of benzene (2 parts) and ethyl acetate (1 part). The 3rdto 7th fractions were concentrated to give 2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-.beta.-oxide(250 mg).

EXAMPLE 6

A solution of m-chloroperbenzoic acid (2.03 g) in chloroform (30 ml) wasadded dropwise to a solution of2,2,2-trichloroethyl-2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(5.0 g) in chloroform (40 ml) at -10°--5° C. under stirring, and thenthe mixture was stirred at -10°--5° C. for 1 hour. After the solid wasfiltered off, the filtrate was washed with a saturated sodiumbecarbonate aqueous solution and water, in turn, and then dried overmagnesium sulfate. After removal of solvent, the residue wascrystallized by adding ethanol. The crystal was filtered andrecrystallized from ethanol to give 2,2,2-trichloroethyl2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-oxide(4.10 g), mp 130°-131° C.

Analysis C₁₈ H₁₈ O₅ N₂ SCl₄ Calcd. C 41.87, H 3.51, M 5.43, S 6.21.Found C 41.80, H 3.45, N 5.50, S 6.44.

EXAMPLE 7

Sodium tungstate (0.02 g) was added to a solution of2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylic acid(3.1 g) in acetic acid (8 ml) at 7°-10° C. under stirring and then tothe mixture was added 30% aqueous hydrogen peroxide (1.2 ml). Themixture was stirred at 7°-10° C. for 1 hour. After the reaction,ice-water (50 ml) was added to the reaction mixture and then extractedwith ethyl acetate. The extract was washed with water and back-extractedwith 5% sodium bicarbonate aqueous solution. The aqueous layer waswashed with ethyl acetate twice, acidified with 5% hydrochloric acid topH 2 and then extracted with ethyl acetate. The extract was washed withwater, dried and concentrated to give powder of2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylicacid-1-oxide (2 g).

Infrared Absorption Spectrum (CHCl₃). 3350, 1795, 1740, 1688 cm⁻¹.

EXAMPLE 8

A solution of m-chloroperbenzoic acid (0.445 g) in chloroform (5 ml) wasadded to a solution of 2,2,2-trichloroethyl3-bromo-3-methyl-7-(2-phenylacetamido) cepham-4-carboxylate (1.21 g)under stirring at -5° to -10° C., and the mixture was stirred for anhour at the same temperature. After the reaction, the reaction mixturewas washed with 5% sodium bicarbonate aqueous solution and with water inturn and then dried. After the solvent was distilled off, the residuewas crystallized by adding ether. Thus obtained crystals wererecrystallized from ethanol to give 2,2,2-trichloroethyl3-bromo-3-methyl-7-(2-phenylacetamido) cepham-4-carboxylate-1-oxide(1.10 g), mp 159° to 161° C. ##STR125##

EXAMPLE 1

2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate-1-oxide(1.12 g) was dissolved in dried methylene chloride (10 ml). To thissolution were added dimethyl aniline (0.36 g) under cooling at -15° C.and then phosphorus pentachloride (0.6 g), and the mixture was stirredfor 3 hours. To the solution was added anhydrous methanol (0.7 g) undercooling at -40° C. and the solution was stirred for 2 hours and furtherstirred for 1 hour at -15° C. After the reaction, precipitated crystalswere collected by filtration, washed with a small amount of methylenechloride and then dried to give 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-aminopenam-3-carboxylate-1-oxide hydrochloride(0.70 g), mp 147° to 154° C. (dec.).

Infrared Absorption Spectrum (Nujol) 1820, 1800, 1760 cm⁻¹.

EXAMPLE 2

2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (10.8 g)was dissolved in dried methylene chloride (300 ml). To this solutionwere added under cooling at -35° C. dried dimethylaniline (3.6 g) andthe phosphorus pentachloride (6.4 g) and the mixture was stirred for 2.5hours at the same temperature. To the solution was added dropwiseanhydrous methanol (6.4 g) at the same temperature and the mixture wasstirred for 1 hour at -15° C. Water (6.5 ml) was added to the solutionand the solution was vigorously stirred for 30 minutes. After thereaction, precipitates were collected by filtration, washed withmethylene chloride and further with ether and then dried to give powdery2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-aminopenam-3-carboxylatehydrochloride (7.3 g).

Infrared Absorption Spectrum (Nujol) 3350-3400, 1790, 1770 cm⁻¹.

EXAMPLE 3

2,2,2-Trichloroethyl2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate(0.53 g) was dissolved in dried methylene chloride (10 ml). To thissolution were added under cooling at -20° to -30° C. dimethylaniline(0.43 g) and then phosphorus pentachloride (0.23 g) and the mixture wasstirred for 1.5 hours. Further, to the solution was added dropwiseanhydrous methanol (0.34 g) and the solution was stirred for 5 hours.Water (7 ml) was added to the solution at 0° C. and the mixture wasstirred for 10 minutes. Aqueous layer was separated from the mixture.The aqueous layer was adjusted to pH 9 by adding 1 N-sodium hydroxideaqueous solution and extracted with ethyl acetate (10 ml). The extractwas dried over magnesium sulfate and the solvent was distilled off. Theresidue was dissolved in a small amount of ethyl acetate and to thesolution were added toluenesulfonic acid monohydrate (0.1 g) and ethylacetate (5 ml). The mixture was cooled and precipitated crystals arecollected by filtration to give 2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl-6-aminopenam-3-carboxylate toluenesulfonate(0.06 g), mp 182° to 185° C. (dec.).

Infrared Absorption Spectrum (Nujol) 2150, 1795, 1750 cm⁻¹. ##STR126##

EXAMPLE 1

To a sodium of ethyl chlorocarbonate (1.95 g) in dried methylenechloride (120 ml) was added dropwise under cooling -5° C. a solution ofN-(1-cyclopropylethoxy)carbonylphenylglycine (4.74 g) and triethylamine(1.83 g) in dried methylene chloride (50 ml). The solution containing amixed anhydride of N-(1-cyclopropylethoxy)carbonylphenylglycine andethyl chlorocarbonate prepared by stirring the above mixture for 1 hourat the same temperature was cooled at -30° to -35° C. To this solutionwere added dropwise a solution of 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-aminopenam-3-carboxylate hydrochloride (6.95 g)and triethylamine (3.0 g) in dried methylene chloride (100 ml), and themixture was stirred for 3 hours. After the reaction was completed, thereaction mixture was washed with 5% hydrochloric acid, water, 5% sodiumbicarbonate aqueous solution and water in turn and then dried. Thesolvent was distilled off to give amorphous, 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)-phenylglycyl]aminopenam-3-carboxylate (9.7 g).

Infrared Absorption Spectrum (CHCl₃) 3410, 1785, 1765, 1690 cm⁻¹.

EXAMPLE 2

To a solution of pivaloyl chloride (1.4 g) in dried methylene chloride(100 ml) was added dropwise under cooling at -5° C. a solution of1H-tetrazol-1-acetic acid (1.81 g) and triethylamine (1.4 g) in driedmethylene chloride (30 ml), and the mixture was stirred for 2 hours atthe same temperature. The solution containing a mixed anhydride of1H-tetrazole-1-acetic acid and pivalic acid prepared above was cooled at-35° C. and to the solution were added dropwise a solution of2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-aminopenam-3-carboxylatehydrochloride (4.0 g) and triethlamine (2.0 g) in dried methylenechloride (80 ml), after which the mixture was stirred for 4 hours at thesame temperature. After the reaction was completed, the reaction mixturewas post-treated in the similar manner as described in Example 1 to giveoily 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)acetamido]penam-3-carbodylate(3.85 g).

Infrared Absorption Spectrum (Film) 3250, 1783, 1765, 1685 cm⁻¹.

EXAMPLE 3

A solution of 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-aminopenam-3-carboxylate hydrochloride (6.95 g)and triethylamine (3.0 g) in dried methylene chloride (100 ml) wascooled at -25° C. To this solution was added dropwise a solution of3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chrolide (4.5 g) indried methylene chloride (30 ml), and the mixture was stirred for 3hours at the same temperature. After the reaction was completed, thereaction mixture was post-treated in the similar manner as described inExample 1 to give oily 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate(6.75 g).

Infrared Absorption Spectrum (Film) 3370, 1790, 1765, 1670 cm⁻¹.

The following compounds were obtained by using the same procedures asthose of the Examples 1 to 3.

    __________________________________________________________________________     ##STR127##                                                                   No.                                                                              R.sup.1'     R.sup.2        R.sup.3                                                                           Y'          X   Property of the            __________________________________________________________________________                                                       product                        ##STR128##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          N.sub.3     S   mp. 105°to                                                             106° C.             2                                                                                 ##STR129##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                           ##STR130## S   Oil Infrared                                                                  Absorption Spectrum(CHC                                                       l.sub.3) 3320,1790,1765                                                       ,1630 cm.sup.-1            3                                                                                 ##STR131##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                           ##STR132## S   Oil Infrared                                                                  Absorption  Spectrum                                                          (CHCl.sub.3) 3400,1790,                                                       1765,1680 cm.sup.-1        4                                                                                 ##STR133##  COOCH.sub.2 OCl.sub.3                                                                        CH.sub.3                                                                           ##STR134## S   Oil Infrared                                                                  Absorption Spectrum(CHC                                                       l.sub.3) 3300,1790,1765                                                       ,1680 cm.sup.-1            5                                                                                 ##STR135##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          SCOCH.sub.3 S   Oil Infrared                                                                  Absorption Spectrum(CHC                                                       l.sub.3) 3390,1790,1765                                                       ,1690 to 1680                                                                 cm.sup.-1                  6                                                                                 ##STR136##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                           ##STR137## S   Oil Infrared                                                                  Absorption Spectrum(CHC                                                       l.sub.3) 3300,1788,1764                                                       , 1675 cm.sup.-1           7                                                                                 ##STR138##  COOCH.sub.2 CCl.sub. 3                                                                       CH.sub.3                                                                           ##STR139## S   Oil Infrared                                                                  Absorption Spectrum(CHC                                                       l.sub.3) 5200,1790,1770                                                       , 1678 cm.sup.-1           8                                                                                 ##STR140##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                           ##STR141## S   Oil Infrared                                                                  Absorption Spectrum                                                           (Film) 3250,1780,1765,                                                        665 cm.sup.-1              9                                                                                 ##STR142##  COOCH.sub.3    CH.sub.3                                                                           ##STR143## S   Oil Infrared                                                                  Absorption Spectrum(Fil                                                       m) 3300,1785,1745,                                                            1690 cm.sup.-1             10                                                                                ##STR144##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                           ##STR145## S   Oil Infrared                                                                  Absorption Spectrum(Fil                                                       m) 3270,1780,1760,                                                            1710,1680 cm.sup.-1        11                                                                                ##STR146##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                           ##STR147## S   Oil Infrared                                                                  Absorption Spectrum(Fil                                                       m) 3270,1760,1710,                                                            1680 cm.sup.-1             12                                                                                ##STR148##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          OCH.sub.3   S   Oil Infrared                                                                  Absorption Spectrum(CHC                                                       l.sub.3) 3360,1785,1757                                                       , 1666 cm.sup.-1           13                                                                                ##STR149##  COOCH.sub.3    CH.sub.3                                                                           ##STR150## S   Oil Infrared                                                                  Absorption Spectrum(CHC                                                       l.sub.3) 3410,1785,1748                                                       ,  1690 cm.sup.-1          14                                                                                ##STR151##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                           ##STR152## S   Amorphous                  15                                                                                ##STR153##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                           ##STR154## S   Amorphous Infrared                                                            Absorption Spectrum(Nuj                                                       ol) 3300,1780,1770                                                            1665 cm.sup.-1             16                                                                                ##STR155##  COOCH.sub.3    CH.sub.3                                                                          OCH.sub.3   S   Oil Infrared                                                                  Absorption Spectrum(CHC                                                       l.sub.3) 3370,1787,1742                                                       ,  1685 cm.sup.-1          17                                                                                ##STR156##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                           ##STR157## S   mp 148° to                                                             149° C.             18                                                                                ##STR158##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          SCN         S   Oil Infrared                                                                  Absorption Spectrum(Fil                                                       m) 1785,1760,  1690                                                           cm.sup.-1                  19                                                                                ##STR159##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          SCN         S   Oil Infrared                                                                  Absorption Spectrum(Fil                                                       m) 1780,1765, 1680                                                            cm.sup.-1                  20                                                                                ##STR160##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          SCN         S   Powder Infrared                                                               Absorption Spectrum(Nuj                                                       ol) 1785,1770  1670                                                           cm.sup.-1                  21                                                                                ##STR161##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          SCN         S   mp 137° to                                                             140° C.             22                                                                                ##STR162##  COOH           CH.sub.3                                                                          SCOCH.sub.3 S   N,N'-dibonzylethylenedi                                                       amine salt                                                                    mp 105° to                                                             107° C.             23                                                                                ##STR163##  COOH           CH.sub.3                                                                           ##STR164## S   N,N'-dibenzylethylenedi                                                       amino salt                                                                    mp 100° C.                                                             (dec.)                     24                                                                                ##STR165##  COOH           CH.sub.3                                                                           ##STR166## S   mp 120°  C.         25                                                                                ##STR167##  COOH           CH.sub.3                                                                           ##STR168## S   N,N"-dibenzlethylenedia                                                       mine salt                                                                     mp 117° to                                                             119° C. (dec.)      26                                                                                ##STR169##  COOH           CH.sub. 2                                                                          ##STR170## S   mp 152° to                                                             154°  C.            27                                                                                ##STR171##  COOH           CH.sub.3                                                                           ##STR172## S   N,N-dibenzylethylenedia                                                       mine salt                                                                     mp 150°  to                                                            152° C. (dec.)      28                                                                                ##STR173##  COOH           CH.sub.3                                                                           ##STR174## S   Sodium salt mp                                                                200° C. (dec.)      29                                                                                ##STR175##  COOH           CH.sub.3                                                                           ##STR176## S   Sodium salt mp                                                                185°to                                                                 186° C. (dec.)      30                                                                                ##STR177##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          SCN                                                                                        ##STR178##                                                                       Colourless powder          31                                                                                ##STR179##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          Br                                                                                         ##STR180##                                                                       mp 114° to                                                             115° C. (dec.)      32                                                                                ##STR181##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          Br                                                                                         ##STR182##                                                                       Amorphous                  33                                                                                ##STR183##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          Br          S   mp 90° to                                                              93° C.              34                                                                                ##STR184##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          Cl          S   mp 104° to                                                             105° C.             35                                                                                ##STR185##  COOH           CH.sub.3                                                                          Br          S   mp 164.5° to                                                           165.5° C.           36                                                                                ##STR186##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          Br          S   Powder                     37                                                                                ##STR187##  COOCH.sub.3    CH.sub.3                                                                          Br          S   Oil Infrared                                                                  Absorption Spectrum                                                           3350,1785,  1748,1690                                                         cm.sup.-1                  38                                                                                ##STR188##                                                                                 ##STR189##    CH.sub.3                                                                          Br          S   Oil                        39                                                                                ##STR190##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          Br          S   Amorphous                  40                                                                                ##STR191##                                                                                 ##STR192##    CH.sub.3                                                                          Br          S   White crystalline                                                             powder                     41                                                                                ##STR193##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          Br          S   Powder                     42 CH.sub.3 SCH.sub.2 CONH                                                                    COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          Br                                                                                         ##STR194##                                                                       mp 71° to                                                              73° C. (dec.)       43                                                                                ##STR195##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          Br                                                                                         ##STR196##                                                                       mp 115° to                                                             116° C. (dec.)      44                                                                                ##STR197##  COOCH.sub.2 CCl.sub.3                                                                        CH.sub.3                                                                          Cl                                                                                         ##STR198##                                                                       mp 130° to                                                             131° C.             __________________________________________________________________________     ##STR199##

EXAMPLE 1

Acetic acid (1 ml) and zinc powder (0.75 g) were added to a solution of2,2,2-trichloroethyl 2-acetylthiomethyl-2-methyl-6-(2-phenylacetamide)penam-3-carboxylic (0.65 g) in dimethylformamide (3 ml) underice-cooling and the mixture was stirred for 2 hours at the sametemperature. After the reaction, the reaction mixture was filtered andthe filtrate was poured into 5% hydrochloric acid (20 ml) and thenextracted with ethy acetate. The extract was washed with water, driedand the solvent was distilled off to give oil (0.365 g). Afterdissolving the oil in acetone (0.7 ml), to this solution was added asolution of N,N'-dibenzyl-ethylenediamine diacetate (0.142 g) in water(5 ml) and precipitated powder was filtered. The powder was purified byreprecipitation method from a mixture of methanol and water to giveN,N'-dibenzyl-ethylenediamine2-acetylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.211 g) mp. 105° to 107° C.

Analysis for C₁₈ H₁₉ N₂ O₅ S₂.1/2C₁₆ H₂₂ N₂.H₂ O Calc'd: C 57.19, H5.87, N 7.69 Found: C 57.18, H 5.58, N 7.44.

Infrared Absorption Spectrum (Nujol) 3300, 1772, 1690, 1670 cm⁻¹

EXAMPLE 2

Acetic acid (1 ml) and zinc powder (0.80 g) were added to a solution of2,2,2-trichloroethyl2-piperidinothiocarbonylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.95 g) in dimethylformamide (5 ml) under ice-cooling and the mixturewas stirred for 1 hour and 40 minutes. After the reaction, zinc powderwas filtered off and the filtrate was poured into ethyl acetate. Thesolution was washed with 3% hydrochloric acid and then with water (fourtimes) and dried over magnesium sulfate. After drying, the solvent wasdistilled off and the residue was dissolved in a small amount ofmethanol. To this solution was added an aqueous solution ofN,N'-dibenzylethylenediamine diacetate and precipitates were collectedby filtration, washed with water to give N,N'-dibenzylethylenediamine2-piperidinothiocarbonylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.30 g), mp. 100° C. (dec.)

Analysis for C₂₂ H₂₆ O₄ N₃ S₃.1/2C₁₆ H₂₂ Calc'd: C 57.03, H 6.22, N 8.87Found: C 57.00, H 5.87, N 8.60.

Infrared Absorption Spectrum (Nujol) 3280, 1777, 1660 cm⁻¹

EXAMPLE 3

2,2,2-Trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.00 g) was dissolved in dimethylformamide (5 ml).To this solution were added acetic acid (0.5 ml) and then zinc powderunder cooling at -15° C. and the mixture was stirred for 6 hours. Afterthe reaction, zinc powder was filtered off and the filtrate was pouredinto ethyl acetate. The solution was washed 4 times with water and driedover magnesium sulfate. After drying, the solvent was distilled off andthe residue was dissolved in a small amount of methanol and thenpulverized by adding water to the solution. The powder was collected byfiltration, washed with water and dried to give2-anilino-methyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylic acid(0.50 g), mp. 120° C.

Analysis for C₂₂ H₂₃ O₄ N₃ S.1/2H₂ O Calc'd: C 60.81, H, 5.56; N 9.67Found: C 60.49, H 5.40, N 9.44.

Infrared Absorption Spectrum (Nujol) 3400, 1780, 1745 cm⁻¹

EXAMPLE 4

2,2,2-Trichloroethyl2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate(0.67 g) was dissolved in dimethylformamide (5 ml). To this solutionwere added acetic acid (0.8 ml) and zinc powder (0.7 g) under cooling at-15° C. and the mixture was stirred for 2 hours at the same temperature.After the reaction, zinc powder was filtered off and the filtrate waspoured into 5% hydrochloric acid (20 ml) and then extracted with ethylacetate. The extract was washed with water, dried and the solvent wasdistilled off. The residue was dissolved in methanol (0.8 ml) and tothis solution was added a solution of N,N'-dibenzylethylenediaminediacetate (0.18 g) in water (5 ml) and precipitates were collected byfiltration, washed with water and dried to giveN,N'-dibenzylethylenediamine2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[3(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate(0.24 g), mp. 117° to 119° C. (dec.).

Infrared Absorption Spectrum (Nujol) 3400, 1778, 1665 cm⁻¹

EXAMPLE 5

2,2,2-Trichloroethyl2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)acetamido]-penam-3-carboxylate (0.6 g) was dissolved indimethylformamide (5 ml). To this solution were added acetic acid (0.9ml) and zinc powder (0.8 g) under cooling at -15° C. and the mixture wasstirred for 1.5 hours at the same temperature. After the reaction, zincpowder was filtered off and the filtrate was poured into 5% hydrochloricacid (20 ml) and then extracted with ethyl acetate. The extract waswashed with water, dried and the solvent was distilled off. The residuewas crystallized from ether to give2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)acetamido]penam-3-carboxylic acid (0.25 g). mp. 152° to 154° C.

Infrared Absorption Spectrum (Nujol) 3230, 1780, 1738, 1692 cm⁻¹

EXAMPLE 6

2,2,2-Trichloroethyl2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.94 g) was dissolved in dimethylformamide (5 ml). To this solutionwere added under ice-cooling acetic acid (0.7 ml) and then zinc powder(0.80 g) under stirring and the mixture was stirred for 2.5 hours. Afterthe reaction, zinc powder was filtered off and the filtrate wasdissolved in ethyl acetate. The solution was washed with 3% hydrochloricacid, 3 times with water and dried over magnesium sulfate. After drying,the solvent was distilled off and the residue was dissolved in a smallamount of methanol and then crystallized by adding an aqueous solutionof N,N'-dibenzylethylenediamine diacetate (0.36 g). Crystals werecollected by filtration and washed with a mixture of ethanol and waterand then dried to give N,N'-dibenzylethylenediamine2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.50 g),mp. 150° to 152° C. (dec.).

Analysis for C₁₈ H₁₈ O₄ N₆ S₂.1/2C₁₆ H₂₂ N₂.1/2H₂ O Calc'd: C 54.48, H5.28, N 17.17 Found: C 54.45, H 5.29, N 17.00.

Infrared Absorption Spectrum (Nujol) 3370, 1763, 1674 cm⁻¹

EXAMPLE 7

2,2,2-Trichloroethyl2-chloromethyl-2-methyl-6.(2-phenylacetamido)penam-3-carboxylate (1.5 g)was dissolved in dried dimethylformamide (8 ml) and to this solutionwere added formic acid (1.5 ml) and then zinc powder (1.5 g) understirring while ice-cooling. After stirring for 2 hours at the sametemperature, zinc powder was filtered off and washed withdimethylformamide (5 ml). The filtrate and the washings were added to amixed cool solution of ethylacetate (30 ml) and 5% hydrochloric acid (15ml). After extracting with ethyl acetate, the extract was washed withwater and dried over magnesium sulfate. The gummy substance (1.16 g)obtained by distilling off the solvent under reduced pressure wascrystallized from a mixed solvent of ethyl acetate and isopropyl etherto give 2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylicacid (660 mg) mp. 110° to 112° C. (dec.).

Analysis for C₁₆ H₁₇ N₂ O₄ SCl Calc'd: 52.10, H 4.65, N 7.60, S 8.69, Cl9.61 Found: C 51.90, H 4.73, N 7.46, S 8.67, Cl 9.84

Infrared Absorption Spectrum (Nujol) 3325, 1788, 1730, 1635 cm⁻¹

EXAMPLE 8

2,2,2-Trichloroethyl2-(benzothiazol-2-yl)thiomethyl-2-methyl-6(2-phenylacetamido)penam-3-carboxylate(0.90 g) was dissolved in dimethylformamide (5 ml). To this solutionwere added acetic acid (0.7 ml) under ice-cooling and then zinc powder(0.80 g) under stirring, and then the mixture was stirred for 2 hours.After zinc powder was filtered off, the filtrate was dissolved in ethylacetate and the solution was washed with 3% hydrochloric acid and then 3times with water and thereafter dried over magnesium sulfate. Theresidue obtained by distilling off the solvent was dissolved in a smallamount of acetone. To this solution was added a solution of sodium2-ethylhexanoate (250 mg) in acetone (5 ml) and the solution was againconcentrated. The residue was crystallized by adding ethanol and thecrystals were collected by filtration, washed with a small amount ofethanol and dried to give sodium2-(benzothizol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.50 g), mp. 200° C. (dec.).

Infrared Absorption Spectrum (Nujol) 3400, 1760, 1670, 1600 cm⁻¹

EXAMPLE 9

2,2,2-trichloroethyl2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate(0.80 g) was dissolved in dimethylformamide (5 ml). To this solutionwere added acetic acid (0.5 ml) and then zinc powder (0.80 g) underice-cooling and the mixture was stirred for 2 hours. Zinc powder wasfiltered off and the filtrate was dissolved in ethyl acetate. Thesolution was washed with 5% hydrochloric acid and then 4 times withwater and thereafter dried over magnesium sulfate. The residue obtainedby distilling off the solvent was dissolved in a small amount of ethylacetate and to the solution was added a solution of sodium2-ethylhexanoate (250 mg) in acetone (5 ml), and then the solution wasconcentrated. The residue was pulverized from ethyl acetate and furtherthe powder was crystallized from ethanol. The crystals were collected byfiltration, washed with ethanol and dried to give sodium2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate(0.28 g), mp 185° to 186° C. (dec.).

Infrared Absorption Spectrum (Nujol) 3200, 1757, 1670, 1625 cm⁻¹

In the similar manner, the following compound was obtained. (1)2-Bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylic acid(mp. 164.5° to 165.5° C.). ##STR200##

EXAMPLE 1

Methyl2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidineacetate(454 mg) was dissolved in methylene chloride (20 ml). To this solutionwas added methanol (5 ml) and thereafter added boron trifluorideetherate (0.124 g) at 0° C. The mixture was stirred for 3 hours at thesame temperature and further stirred for 2 hours at 5° to 10° C. Afterthe reaction, the mixture was washed with 5% sodium bicarbonate aqueoussolution and with water. After drying the mixture, the mixture wasconcentrated and the oily residue (250 mg) was purified by columnchromatography on silica gel to give oily methyl3-methyl-3-methoxy-7-(2-phenoxyacetamido)-cephem-4-carboxylate.

Infrared Absorption Spectrum (CHCl₃) 3400, 1772, 1739, 1688 cm⁻¹

EXAMPLE 2

Methyl2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-acetidineacetate(1.06 g) was dissolved in methylene chloride (20 ml). To this solutionwere added aniline (0.28 g) and then silver fluoroborate (0.80 g) andthereafter the mixture was stirred for 2 days at room temperature. Afterthe reaction, the reaction mixture was filtered and the filtrate waswashed with a dilute phosphoric acid aqueous solution and then withwater. After drying the mixture, the mixture was concentrated and theresidue was purified by column chromatography on silica gel (25 g) togive methyl 3-methyl-3-anilino-7(2-phenoxyacetamido)cepham-4-carboxylate(0.38 g), mp. 129° to 130° C.

EXAMPLE 3

2,2,2-Trichloroethyl2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isoproponyl-1-acetidinoacetate(1.26 g) was dissolved in ethyl acetate (15 ml). To this solution wasadded acetic acid (5 ml) and then silver acetate (0.68 g) under stirringat room temperature. The mixture was stirred for 4 hours at the sametemperature. After the reaction, the reaction mixture was filtered andthe filtrate was washed with water and then with 5% sodium bicarbonateaqueous solution. The solution was filtered again and the filtrate waswashed with water and then dried. The solvent was distilled off and theresidue was purified by thin layer chromatography using a mixture ofacetone: benzene (1:9) to give amorphous 2,2,2-trichloroethyl3-acetoxy-3-methyl-7-(2-phenylacetamido)cephem-4-carboxylate.

Infrared Absorption Spectrum (CHCl₃) 3425, 1780, 1750, 1680 cm⁻¹

EXAMPLE 4

Methyl2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(2.12 g) was dissolved in methanol (80 ml). To this solution was addedsilver nitrate (0.68 g) and the mixture was refluxed for 28 hours. Afterthe reaction, precipitates were filtered and the filtrate wasconcentrated. The obtained residue was extracted with ethyl acetate andthe extract was washed with water and then dried. The solvent wasdistilled off and the obtained residue was purified by columnchromatography on silica gel using chloroform as developing solvent togive pale yellow oil of methyl3-methoxy-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (620 mg.).

Infrared Absorption Spectrum (CHCl₃) 3400, 1772, 1739, 1688 cm⁻¹

Similar result was obtained using methylene chloride as solvent andsilver fluoroborate instead of silver nitrate.

EXAMPLE 5

Methyl2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-acetidineacetate(0.53 g) was idssolved in methanol (20 ml). To this solution was addedsilver acetate (0.17 g) and the mixture was refluxed for 39 hours. Afterthe reaction, the reaction mixture was post-treated in the similarmanner as described in Example 1 to give oily methyl3-methyl-3-methoxy-7-(2-phenoxyacetamido)-cepham-4-carboxylate (200 mg).

EXAMPLE 6

A mixture of methyl2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidineacetate(0.53 g), mercuric acetate (0.3 g) and methanol (20 ml) were refluxedfor 48 hours. After the reaction, the reaction mixture was post-treatedin the similar manner as described in Example 1 to give oily methyl3-methyl-3-methoxy-7-(2-phenoxyacetamido)cephem-4-carboxylate (180 mg).

EXAMPLE 7

Methyl2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(0.53 g) was dissolved in methanol (20 ml). To this solution was addedmercuric chloride (0.27 g) and the mixture was refluxed for 24 hours.After the reaction, the reaction mixture was post-treated in the similarmanner as described in Example 1 to give oily methyl3-methyl-3-methoxy-7-(2-phenoxyacetamido)cepham-4-carboxylate (220 mg).

EXAMPLE 8

Methyl2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(0.53 g) was dissolved in methanol (20 ml). To this solution was addedcupric oxide (0.15 g), and the mixture was refluxed for 72 hours. Afterthe reaction, the reaction mixture was post-treated in the similarmanner as described in Example 1 to give oily methyl3-methyl-3-methoxy-7-(2-phenoxyacetamido)cephem-4-carboxylate (50 mg).

EXAMPLE 9

2,2,2-Trichloroethyl2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate(0.63 g) and p-toluenesulfonic acid monohydrate (0.19 g) were dissolvedin a mixture of methanol (15 ml) and methylene chloride (5 ml). Themixture was stirred for 4.5 hours at 50° C. After the reaction, methanoland methylene chloride were distilled off and the residue was dissolvedin ethyl acetate (10 ml). The ethyl acetate layer was washed with asaturated sodium bicarbonate aqueous solution and then with water andthereafter dried over magnesium sulfate. The residue obtained byremoving the solvent was purified by column chromatography on silica gelusing chloroform as developing solvent to give 2,2,2-trichloroethyl3-methyl-3-methoxy-7-(2-phenylacetamido)-cephem-4-carboxylate (120 mg),mp. 132° to 133° C.

The following compounds were obtained by using the same procedures asthose of the Examples 1 to 9.

(1) 2,2,2-Trichloroethyl3-methyl-3-azido-7-(2-phenylacetamido)cepham-4-carboxylate (mp. 136° to140° C.).

(2) 2,2,2-Trichloroethyl3-methyl-3-hydroxy-7-(2-phenylacetamido)cepham-4-carboxylate (mp. 169°to 171° C.).

(3) 2,2,2-Trichloroethyl3-methyl-3-isopropoxy-7-(2-phenylacetamido)cepham-4-carboxylate (oil).

(4) 1-Cyclopropylethyl3-methyl-3-anilino-7-(2-phenylacetamido)cepham-4-carboxylate (colorlessoil).

(5) 2,2,2-Trichloroethyl 3-methyl-3-anilino-7-(2-phenylacetamido)cephem-4-carboxylate (oil).

(6) 3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylic acid(mp. 119° to 123° C. (dec). ##STR201##

EXAMPLE 1

A mixture of 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6(2-phenylacetamido)penam-3-carboxylate (1.08 g),sodium azide (0.26 g), acetone (20 ml) and water (4 ml) was stirred for4 hours at room temperature. After acetone was distilled off underreduced pressure, the residue was extracted with ethyl acetate. Theethyl acetate layer was washed with water, with saturated sodiumbicarbonate aqueous solution and further with water and then dried overmagnesium sulfate. The solvent was distilled off under reduced pressureand a small quantity of ether was added to the residue to give colorlesscrystals of 2,2,2-trichloroethyl3-azido-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (170 mg).This substance was recrystallized from carbon tetrachloride to givecrystals melting at 136° to 140° C.

Infrared Absorption Spectrum (Nujol) 3310, 2110, 1770, 1746, 1658 cm⁻¹

EXAMPLE 2

2,2,2-Trichloromethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g)was dissolved in absolute dimethylsulfoxide (5 ml). To this solution wasadded silver fluoroborate (0.20 g) and then the mixture was stirredunder shielding from light for 3 hours at room temperature. To thesolution was added a solution of triethylamine (0.1 g) indimethylsulfoxide (0.5 ml) and the solution was further stirred for 5hours and then allowed to stand overnight at room temperature.Precipitates were filtered off and the filtrate was poured intoice-water and then extracted with ethyl acetate. The extract was washedwith water and dried. The residue obtained by distilling off the solventunder reduced pressure was crystallized by a small amount of ether togive colorless crystals of 2,2,2-trichloroethyl3-hydroxy-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (280 mg)(58%). This substance was recrystallized from a mixed solvent ofbenzene-n-hexane to give colorless needles melting at 169° to 171° C.

Analysis for C₁₈ H₁₉ N₂ O₅ SCl₃ Calc'd: C 44.87, H 3.97, N 5.81, S 6.66,Cl 22.08 Found: C 45.08, H 3.93, N 5.75, S 6.45, Cl 21.96.

EXAMPLE 3

2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.55g) was dissolved in a mixture of tetrahydrofuran (5 ml) and methanol (5ml). To this solution was added silver fluoroborate (0.24 g) undercooling and then the mixture was stirred for 1 hour. The reactionmixture was concentrated and the obtained residue was dissolved inchloroform. This solution was washed with a saturated sodium bicarbonateaqueous solution and with water and dried over magnesium sulfate. Theresidue obtained by distilling off the solvent was subjected tochromatography on silica gel using chloroform as developing solvent. Theobtained crystals were recrystallized from carbon tetrachloride to give2,2,2-trichloroethyl3-methyl-3-methoxy-7-(2-phenylacetamido)-cephem-4-carboxylate (0.27 g),mp. 132° to 133° C.

The similar result was obtained using methylene chloride instead oftetrahydrofuran in the above example.

Infrared Absorption Spectrum (Nujol) 3300, 1780, 1760, 1683 cm⁻¹

EXAMPLE 4

2,2,2-Trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.55 g)was dissolved in a mixture of tetrahydrofuran (5 ml) and isopropanol (5ml). To this solution was added silver fluoroborate (0.24 g) underice-cooling and the mixture was stirred for 1 hour. The reaction mixturewas concentrated and the obtained residue was dissolved in chloroform.This solution was washed with a saturated sodium bicarbonate aqueoussolution and with water and then dried over magnesium sulfate. Theresidue obtained by distilling off the solvent was purified bychromatography on silica gel using chloroform as developing solvent togive oily 2,2,2-trichloroethyl3-methyl-3-isopropoxy-7-(2-phenylacetamido)-cepham-4-carboxylate (0.10g).

Infrared Absorption Spectrum (Film) 3300, 1760, 1750, 1670 cm⁻¹

EXAMPLE 5

Methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido) penam-3-carboxylate(0.88 g) was dissolved in methylene chloride (13 ml) containingmethanol. To the solution was added silver fluoroborate (0.45 g), andthe mixture was stirred for 2 hours. After the reaction, the reactionmixture was filtered and the filtrate was washed with a dilute sodiumbicarbonate aqueous solution and then with water. The solution was driedover magnesium sulfate and concentrated. The residue was subjected tocolumn chromatography on silica gel (25 g) and eluted with chloroform.The elute was separated into fractions of each about 20 ml and theseventh to tenth fractions were collected. The solvent was distilled offto give Methyl3-methoxy-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (0.60 g).

Infrared Absorption Spectrum (CHCl₃) 3400, 1772, 1739, 1688 cm⁻¹

The following compounds were obtained by using the same procedures asthose of the Examples 1 to 5.

(1) Methyl 3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate(mp. 129° to 130° C.).

(2) 1-Cyclopropylethyl3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (colorlessoil).

(3) 2,2,2-Trichloroethyl3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (oil).

(4) 3-anilino-3-methyl-7-(2-phenoxyacetamido)-cepham-4-carboxylic acid.##STR202##

EXAMPLE 1

Anilino (0.28 g) was added to a solution of 2,2,2-trichloroethyl3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (1.10 g) inmethylene chloride (15 ml). To the solution was added silver fluoborate0.45 g under ice-cooling under stirring and stirred at the sametemperature for 4 hours. After the reaction, the mixture was filteredand the filtrate was washed with dilute phosphoric acid aquous solutionand water in turn. The solution was dried over magnesium sulphate andconcentrated. The residue was subjected to column chromatography onsilica gel (25 g) using chloroform. The 12th to 13th fractions offractions, each of which was separated into 20 cc, were concentrated togive oily 2,2,2-trichlocoethyl 3-anilino-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate.

Infrared Absorption Spectrum (CHCl₃) 3420, 1772, 1750, 1680 cm⁻¹

The following compounds were obtained by using the same procedure asthat of the Example 1.

    __________________________________________________________________________                                             Property of                          No.                                                                              R.sup.1        R.sup.2  R.sup.3                                                                           Y         the product                          __________________________________________________________________________        ##STR203##    COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          N.sub.3   mp. 136°-140° C.       2                                                                                 ##STR204##    COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          OH        mp. 169°-171° C.       3                                                                                 ##STR205##    COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                          OCH.sub.3 mp. 132°-133° C.       4                                                                                 ##STR206##    COOCH.sub.2 CCl.sub.3                                                                  CH.sub.3                                                                           ##STR207##                                                                             oily                                 5                                                                                 ##STR208##    COOCH.sub.3                                                                            CH.sub.3                                                                          OCH.sub.3 oily                                 6                                                                                 ##STR209##    COOCH.sub.3                                                                            CH.sub.3                                                                           ##STR210##                                                                             mp. 129°-130° C.       7                                                                                 ##STR211##                                                                                   ##STR212##                                                                            CH.sub.3                                                                           ##STR213##                                                                             colorless oily                       8                                                                                 ##STR214##    COOH     CH.sub.3                                                                           ##STR215##                                                                             mp. 119°-123° C.                                                (dec)                                __________________________________________________________________________     ##STR216##

EXAMPLE 1

1-Cyclopropylethyl2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate(0.4 g) was dissolved in dried methylene chloride (10 ml). To thissolution was added dropwise a solution of boron trifluoride etherate (50mg) in dried methylene chloride (3 ml) at 0° C. and the mixture wasstirred for 5 hours at the same temperature. After the reaction, thereaction mixture was washed with 5% sodium bicarbonate aqueous solutionand several times with water and then dried. The oil obtained bydistilling off the solvent was purified by column chromatography onsilica gel using chloroform as developing solvent to give colorless oilof 1-cyclopropylethyl3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (198 mg.).

Infrared Absorption Spectrum (Film) 3300, 1777, 1740, 1690 cm⁻¹

EXAMPLE 2

Methyl2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate(170 mg) was dissolved in dried methylene chloride (4 ml). To thissolution was added dropwise a solution of boron trifluoride etherate (25mg) in dried methylene chloride (2 ml) under ice-cooling and the mixturewas stirred for 1 hour at the same temperature. After reaction, thereaction mixture was washed with 5% sodium bicarbonate aqueous solutionand with water and then dried. The oil obtained by distilling off thesolvent was subjected to column chromatography on silica gel usingchloroform as developing solvent to give methyl3-anilino-3-methyl-7-(2-phenoxyacetamido)-cepham-4-carboxylate (80 mg),mp 129° to 130° C., from the fifth to eighth fractions of fractions eachof which was separated into 50 ml.

Infrared Absorption Spectrum (CHCl₃) 3420, 1775, 1736, 1691 cm⁻¹

In the similar manner, the following compound was obtained.

(1) 3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylic acid(mp 119° to 123° C. (dec)) ##STR217##

EXAMPLE 1

1-Cyclopropylethyl3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (142 mg)was dissolved in ice-cooled trifluoroacetic acid (1.5 ml) and themixture was stirred for 1 hour under ice-cooling. After the reaction,the reaction mixture was concentrated under reduced pressure. Theresidue was dissolved by adding ethyl acetate and extracted with 5%sodium bicarbonate aqueous solution. The extract was adjusted to pH 2with 5% hydrochloric acid and back-extracted with ethyl acetate. Theextract was washed with water, dried and the solvent was distilled off.The residue (amorphous) was dissolved in methanol and to this solutionwas added water little by little. Precifitates were collected byfiltration and dried to give powder of3-anilino-3-methyl-7-(2-phenoxy-acetamido)cepham-4-carboxylic acid (62mg), mp 119° to 123° C. (dec.).

Analysis for C₂₂ H₂₃ O₅ N3S. 3/2 H₂ O Calc'd C 56.40, H 4.95, N 8.97Found C 56.57, H, 5.05, N 8.97.

IR spectrum (Nujol) 3300, 1770, 1735, 1665 cm⁻¹

In the similar manner, the following compound was obtained.

(1) 3-bromo-3-methyl-7-(2-phenoxy-acetamido)cepham-4-carboxylic acid(amorphous). ##STR218##

EXAMPLE 1

5-Methyl-1,3,4-thiadiazole-2-thiol (0.16 g) was dissolved in a mixtureof pH 6.5 phosphate buffer (5 ml) and acetone (10 ml). To the solutionwas added 2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g)and the mixture was stirred for 3 hours at room temperature. Thereaction mixture was extracted with ethyl acetate and the ethyl acetatelayer was washed with sodium bicarbonate aqueous solution and with waterand then dried over magnesium sulfate. The solvent was distilled offfrom the extract and the residue was purified by column chromatographyon silica gel using chloroform as developing solvent to give2,2,2-trichloroethyl2-oxo-3-(2-phenylacetamido)-4-(5-methyl-1,3,4-thiadiazol-2-yl)dithio-.alpha.-propenyl-azetidineacetate(0.24 g), mp 108° to 109° C., from the fifth to ninth fractions offractions each of which was separated into 30 ml.

Infrared Absorption Spectrum (Nujol) 3280, 1788, 1760, 1654 cm⁻¹

EXAMPLE 2

2-Mercaptobenzothiazole (0.20 g) was dissolved in a mixture of pH 6.7phosphate buffer (15 ml) and dioxane (15 ml). To the solution was added2,2,2-trichloroethyl2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g)and the mixture was stirred for 7 hours at room temperature. Dioxane wasdistilled off from the mixture and the residue was extracted with ethylacetate. The ethyl acetate layer was washed with 2% potassium carbonateaqueous solution and with water and then dried over magnesium sulfate.The residue obtained by distilling off the solvent was purified bycolumn chromatography on silica gel using chloroform as developingsolvent to give 2,2,2-trichloroethyl2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-propenyl-1-azetidineacetate(0.10 g), mp 140° to 141° C., from the fourth to sixth fractions offractions each of which was separated into 30 ml.

EXAMPLE 3

5-Methyl-1,3,4-thiadiazole-2-thiol (0.4 g) was dissolved in a mixture ofpH 7.3 phosphate buffer (20 ml) and acetone (20 ml). To the solution wasadded a solution of methyl 2-bromomethyl2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.80 g) in acetone(10 ml) and the mixture was stirred for 4 hours at room temperature.After the reaction was completed, acetone was distilled off from thereaction mixture and the residue was extracted with ethyl acetate. Theextract was washed with sodium bicarbonate aqueous solution and withwater, dried over magnesium sulfate and then the solvent was distilledoff. The residue was subjected to column chromatography on silica gel(60 g) and eluted with chloroform. The eluate was separated into about30 ml fraction to give oily methyl2-oxo-3-(2-phenoxyacetamido)-4-(5-methyl-1,3,4-thiadiazol-2-yl)dithio-.alpha.-propenyl-azetidineacetate(0.22 g) from the eleventh to thirteenth fractions.

Infrared Absorption Spectrum (Chloroform) 3430, 1779, 1742, 1692 cm⁻¹Further, oily4,4-dithiobis[methyl-2-oxo-3-(2-phenoxyacetamido)-α-propenyl-1-azetidineacetate](0.30g) was obtained from the eighth to tenth fractions of the abovefractions.

Infrared Absorption Spectrum (Film) 3280, 1770, 1740, 1680 cm⁻¹

    __________________________________________________________________________     ##STR219##                                                                                                                         Property of             No.                                                                              R.sup.1             R.sup.2       R.sup.3                                                                           R.sup.4      the                     __________________________________________________________________________                                                          product                     ##STR220##         COOH          CH.sub.3                                                                           ##STR221##  mp 142° to                                                             144° C.          2                                                                                 ##STR222##         COOCH.sub.2 CCl.sub.3                                                                       "   "            mp 108° to                                                             109° C.          3                                                                                 ##STR223##         COOCH.sub.3   "                                                                                  ##STR224##  mp 146° to                                                             147° C.          4    "                 COOH          "   "            mp 146° to                                                             148° C.                                                                (dec.)                  5    "                 COOCH.sub.2 CCl.sub.3                                                                       "   "            mp 171° to                                                             174.5° C.        6                                                                                 ##STR225##         COOCH.sub.2 CCl.sub.3                                                                       "   "            mp 159° to                                                             161° C.          7                                                                                 ##STR226##                                                                                        ##STR227##   "   "            Oil                     8                                                                                 ##STR228##         COOH          "   "            mp 76° to                                                              80° C.           9    "                                                                                                ##STR229##   "   "            mp 114° to                                                             117° C.          10                                                                                ##STR230##         COOCH.sub.2 CCl;.sub.3                                                                      "   "            Amorphous               11                                                                                ##STR231##         "             "   "            Oil                     12                                                                                ##STR232##         "             "   "            Amorphous               13                                                                                ##STR233##         "             "   "            mp 136° to                                                             137° C.          14                                                                                ##STR234##         "             "   "            mp 164° to                                                             165° C.          15 NCCH.sub.2 CONH     "             "   "            mp 117° to                                                             119° C.          16                                                                                ##STR235##                                                                                        ##STR236##   "   "            mp 149° tp                                                             152° C.          17                                                                                ##STR237##         COOCH.sub.2 CCl.sub.3                                                                       "   "            mp 175° to                                                             176° C.          18                                                                                ##STR238##                                                                                        ##STR239##   "   "            mp 127° to                                                             129° C.          19   "                 COOCH.sub.3   "                                                                                  ##STR240##  Oil                     20   "                 "             "   SCOCH.sub.3  Oil                     21   "                 "             "                                                                                  ##STR241##  Oil                     22   "                 "             "                                                                                  ##STR242##  Oil                     23   "                 "             "                                                                                  ##STR243##  Oil                     24                                                                                ##STR244##         COOCH.sub.2 CCl.sub.3                                                                       "                                                                                  ##STR245##  Oil                     __________________________________________________________________________

What is claimed is:
 1. A compound of the general formula: ##STR246##wherein R¹ is amino, R² is carboxy or a conventionally protectedcarboxy, X is --S-- or ##STR247## R³ is lower alkyl and Y" isthiocyanato.
 2. The compound according to claim 1, in which R² iscarboxy, lower alkoxycarbonyl, trihalo(lower)alkoxycarbonyl or carboxysalt.
 3. The compound according to claim 2, in which R² is carboxy,methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl or a carboxy salt withN,N'-dibenzylethylenediamine, R³ is a methyl and X is --S--.
 4. Thecompound according to claim 3, which is 2,2,2-trichloroethyl2-thiocyanatomethyl-2-methyl-6-aminopenam-3-carboxylatetoluenesulfonate.